Hydrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof

ABSTRACT

New hydrate forms of alendronate sodium, having water content of between about one and about twelve percent, and processes for their manufacture, are disclosed. New crystalline forms of alendronate sodium B, D, E, F, G and H, and processes for manufacturing them, are also disclosed. These new forms of alendronate sodium are suitable for incorporation into pharmaceutical compositions for combating bone resorption in bone diseases.

This application is a continuation of application Ser. No. 09/384,145filed Aug. 27, 1999, now U.S. Pat No. 6,281,381.

FIELD OF THE INVENTION

This invention relates to new hydrate and crystalline forms ofalendronate sodium, processes for the manufacture thereof, andpharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

Alendronate sodium, the sodium salt of alendronic acid, also known as4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium, has theformula I:

It is an agent for combating bone resorption in bone diseases includingosteoporosis and Paget's disease.

Various methods for preparing alendronic acid are known in the art andhave been disclosed in M. I. Kabachnik et al., Synthesis and Acid-Baseand Complexing Properties of Amino-Substitutedα-Hydroxyalkylidene-diphosphonic Acids, Izv. Akad. Nauk USSR, Ser. Khim,2,433 (1978) and in U.S. Pat. Nos. 4,407,761, 4,621,077, 4,705,651,5,039,819 and 5,159,108.

U.S. Pat. No. 4,922,007 describes the preparation of a trihydrate ofalendronate sodium by reaction of 4-aminobutyric acid with phosphorousacid and phosphorous trichloride in the presence of methanesulfonic acidfollowed by the addition of sodium hydroxide.

The present invention provides new forms of alendronate sodium, havingwater content of 1.3 to 11.7 percent, and processes for theirmanufacture. Moreover, the present invention provides new crystallineforms of alendronate sodium, designated forms B, D, E, F, G and H, andprocesses for the manufacture thereof.

OBJECTS AND SUMMARY OF THE INVENTION

The present invention provides novel hydrate forms of alendronate sodiumhaving water content of between 1.3 and 11.7 percent water. Typically,but without limitation, the present invention relates to the followingnovel hydrate forms of alendronate monosodium: 1/4 hydrate, 1/3 hydrate,hemihydrate, 2/3 hydrate, 3/4 hydrate, monohydrate, 5/4 hydrate, 4/3hydrate, 3/2 hydrate, 5/3 hydrate, 7/4 hydrate and dihydrate.

The present invention provides a new crystalline Form B of alendronatesodium, having a powder X-ray diffractogram substantially as depicted inFIG. 1a, with characteristic peaks at 12.2±0.2, 13.3±0.2, 14.8±0.2,15.8±0.2, 16.3±0.2, 16.6±0.2, 17.2±0.2, 19.4±0.2, 21.3±0.2, 22.6±0.2,23.2±0.2, 24.0±0.2, 25.2±0.2, 25.8±0.2, 27.4±0.2, 29.4±0.2, and 36.0±0.2degrees 2 theta. Alendronate sodium Form B has significant IR bands asdepicted in FIG. 1c at 654 cm⁻¹, 955 cm^(−1,) 1074 cm-1, 1261 cm⁻¹, 1309cm⁻¹, and 1614 cm⁻¹. The TGA curve, FIG. 1b, shows a clear two-step losson drying of 7.2%, which implies that the crystal form B contains astoichiometric quantity of water close to that of the monohydrate(expected loss on drying value: 6.2%).

Another embodiment of the invention is a new crystalline Form D ofalendronate sodium, having a powder X-ray diffractogram substantially asdepicted in FIG. 4a, with characteristic peaks at 13.1±0.2, 15.2±0.2,16.3±0.2, 18.4±0.2, 20.8±0.2, 22.3±0.2, 22.5±0.2, 23.4±0.2, 23.7±0.2,31.4±0.2, and 35.7±0.2 degrees 2 theta. Form D as depicted in FIG. 4 chas significant IR bands at 662 cm⁻¹, 919 cm⁻¹, 934 cm⁻¹, 954 cm⁻¹, 1054cm⁻¹, 1072 cm⁻¹ 1297 cm⁻¹ and 1318 cm⁻¹. The TGA curve, as depicted inFIG. 4b, shows a gradual loss on drying of 4.1% up to 180° C.

An additional embodiment is a new crystalline Form E of alendronatesodium, having a powder X-ray diffractogram substantially as depicted inFIG. 5a, with characteristic peaks at 7.0±0.2, 9.3±0.2, 11.8±0.2,13.3±0.2, 14.0±0.2, 15.3±0.2, 16.2±0.2, 19.4±0.2 degrees 2 theta. Form Ehas significant IR bands as depicted in FIG. 5c at 660 cm⁻¹, 897 cm⁻¹,924 cm⁻¹, 953 cm⁻¹, 970 cm⁻¹, 1017 cm⁻¹, 1040 cm⁻¹, 1093 cm⁻¹ 1149 cm⁻¹,1177 cm⁻¹, 1252 cm⁻¹ 1293 cm⁻¹ 1337 cm⁻¹, 1535 cm⁻¹, 1606 cm⁻¹, and 1639cm⁻¹. The TGA curve, as depicted in FIG. 5b, shows a gradual loss ondrying of 3.7% up to 150° C.

A still further embodiment of the invention is a new crystalline Form Fof alendronate sodium, having a powder X-ray diffractograrnsubstantially as depicted in FIG. 6a, with characteristic peaks at9.3±0.2, 11.7±0.2, 13.0±0.2, 13.4±0.2, 14.2±0.2, 15.3±0.2, 16.2±0.2,17.4±0.2, 19.1±0.2, 19.4±0.2 and 25.5±0.2 degrees 2 theta. Form F hassignificant IR bands as depicted in FIG. 6c at 660 cm⁻¹, 893 cm⁻¹, 930cm⁻¹, 953 cm⁻¹, 970 cm⁻¹, 982 cm⁻¹, 1010 cm⁻¹, 1033 cm⁻¹ 1052 cm⁻¹, 1060cm⁻¹, 1069 cm⁻¹, 1109 cm⁻¹ and 1169 cm⁻¹, 1251 cm⁻¹, 1338 cm⁻¹, 1498cm⁻¹, 1544 cm⁻¹, 1603 cm⁻¹, 1637 cm⁻¹, 1664 cm⁻¹. The TGA FIG. 6b curveshows a gradual loss on drying of 1.3% up to 150° C.

A further embodiment is a new crystalline Form G of alendronate sodium,having a powder X-ray diffractogram substantially as depicted in FIG.7a, with characteristic peaks at 9.5±0.2, 10.1±0.2, 12.7±0.2, 16.2±0.2,17.3±0.2, 17.6±0.2, 19.1±0.2, 20.4±0.2, 20.9±0.2, 22.1±0.2, 24.8±0.2,25.5±0.2, 28.0±0.2, 29.0±0.2, 29.6±0.2, 30.4±0.2, 32.4±0.2, and 32.8±0.2degrees 2 theta. Form G has significant IR bands as depicted in FIG. 7cat 665 cm⁻¹, 751 cm⁻¹, 856 cm⁻¹, 895 cm⁻¹, 913 cm⁻¹, 939 cm⁻¹, 1011cm⁻¹, 1021 cm⁻¹, 1050 cm⁻¹, 1091 cm⁻¹, 1155 cm⁻¹, 1273 cm⁻¹, 1305 cm⁻¹,1337 cm⁻¹, 1510 cm⁻¹, and 1639 cm⁻¹. The TGA curve, FIG. 7b, shows aloss on drying of 6.5% which indicates that the crystal form G containsa stoichiometric quantity of water corresponding to that of themonohydrate (expected loss on drying value: 6.2%). This TGA step issharp and occurs at 195° C. The relatively high temperature ofdehydration implies that the water is bound tightly to the alendronatemolecule. The dehydration step is immediately followed by another stepdue to decomposition. Due to the decomposition process that occursadjacent to the dehydration, the conventional loss of drying method isnot feasible, and for loss on drying determination the TGA is used.

Yet another embodiment is a new crystalline Form H of alendronatesodium, having a powder X-ray diffractogram substantially as depicted inFIG. 8a, with characteristic peaks at 9.2±0.2, 13.0±0.2, 14.2±0.2,15.0±0.2, 17.1±0.2, 20.7±0.2, 22.0±0.2, 22.4±0.2, degrees two theta.Form H has significant IR bands, as depicted in FIG. 8c, of 664 cm⁻¹,688 cm⁻¹, 722 cm⁻¹, 751 cm⁻¹, 863 cm⁻¹, 893 cm⁻¹, 918 cm⁻¹, 936 cm⁻¹,984 cm⁻¹, 1010 cm⁻¹, 1036 cm⁻¹, 1052 cm⁻¹, 1092 cm⁻¹, 1157 cm⁻¹, 1273cm⁻¹, 1303 cm⁻¹ and 1338 cm⁻¹, 1499 cm⁻¹, 1598 cm⁻¹, 1636 cm⁻¹, and 1664cm⁻¹. The TGA curve FIG. 8b shows a sharp loss on drying of 3.7% at 170°C.

All of sodium alendronate crystalline forms B, D, E, F, G and H containwater in the amount of 2.2 to 9.0% by weight.

The invention further provides a new hydrate form of alendronate sodiumhaving a water content of 1.3% to 3.1%.

A further embodiment is a new hydrate form of alendronate sodium havinga water content of 2.5% to 3.5%.

A further embodiment is a new hydrate form of alendronate sodium havinga water content of 2.8% to 3.9%.

An additional embodiment is a new hydrate form of alendronate sodiumhaving a water content of 3.2% to 5.8%.

Another embodiment is a new hydrate form of alendronate sodium having awater content of 5.1% to 7.0%.

A still further embodiment is a new hydrate form of alendronate sodiumhaving a water content of 6.4% to 9.0%.

The invention also provides a new crystalline Form B of alendronatesodium, having a water content of 6.4% to 9.0%.

The invention further provides a new crystalline Form D of alendronatesodium, having a water content of 3.2% to 5.8%.

The invention further provides a new crystalline Form F of alendronatesodium, having a water content of 1.3% to 3.1%.

The invention further provides a new crystalline Form G of alendronatesodium, having a water content of 5.1% to 7.0%.

The invention further provides a new crystalline Form E of alendronatesodium, having a water content of 2.8% to 3.9%.

The invention further provides a new crystalline Form H of alendronatesodium, having a water content of 2.5% to 3.7%.

The invention provides a new monohydrate and a new dehydrate ofalendronate sodium, having an X-ray diffractogram substantially asdepicted in FIGS. 2a and 3 a, accordingly, with characteristic peaks at9.3±0.2, 12.4±0.2, 13.5±0.2, 17.1±0.2, 18.5±0.2, 19.7±0.2, 20.3±0.2,21.0±0.2, 21.8±0.2, 23.4±0.2, 24.3±0.2, 24.9±0.2, 26.3±0.2, 30.0±0.2,and 34.4±0.2 degrees 2 theta. Form C as depicted in FIGS. 2b and 3 b hassignificant IR bands at 660 cm⁻¹, 745 cm⁻¹, 865 cm⁻¹, 913 cm⁻¹, 952cm⁻¹, 966 cm⁻¹, 1017 cm⁻¹, 1046 cm⁻¹, 1128 cm⁻¹, 1174 cm⁻¹, 1235 cm⁻¹,1340 cm⁻¹, 1402 cm⁻¹, 1544 cm⁻¹, 1606 cm⁻¹, and 1644 cm⁻¹. The TGA curveof the monohydrate Form C (FIG. 2b shows a loss on drying of 5.6% whichimplies that the crystal Form C contains a stoichiometric quantity ofwater close to that of the monohydrate (expected loss on drying value:6.2%). The TGA curve of the dehydrate Form C (FIG. 3b) shows a sharp Closs on drying of 12.0% which implies that the crystal Form C contains astoichiometric quantity of water corresponding to dehydrate (expectedloss on drying value: 11.7%).

The present invention also relates to the method of preparing thecompound 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodiumsalt having water content of 1.3% to 11.7% by reacting alendronic acidwith one equivalent of sodium base in an aqueous organic solventselected from the group consisting of. acetone, DMSO, DMF, acetonitrile,alcohols, polyalcohols and/or their ethers, pyridine, sulfolane, -methylpyrrolidinone and dioxane.

The invention further provides a method for making Form D of alendronatesodium, comprising treating alendronic acid anhydrous in a lower alkanolwith 1 equivalent of sodium base and 0 to 4 equivalents of water,followed by isolating the crystalline alendronate sodium Form D.

The invention further provides a method for making Form E of alendronatesodium, comprising treating alendronic acid, which is in anhydrous ormonohydrate form, in a lower alkanol with 1 equivalent of sodium baseand 9 to 15 equivalents of water, followed by isolating the crystallinealendronate sodium Form E.

The invention further provides a method for making Form F of alendronatesodium, comprising treating alendronic acid, in a lower alkanol with 1equivalent of sodium base and 5 to 8 equivalents of water for anhydrousform and 3 to 20 equivalents of water for monohydrate form, followed byisolating the crystalline alendronate sodium Form F.

The invention further provides a method for making alendronate sodiummonohydrate, comprising treating alendronic acid, in a lower alkanolwith 1 equivalent of sodium base and water under the conditionsdescribed hereinafter, followed by isolating the alendronate sodiummonohydrate.

The invention further provides a method for making Form G of alendronatesodium, comprising treating alendronic acid, in a lower alkanol with 1equivalent of sodium base and water under the conditions describedhereinafter, followed by isolating the crystalline alendronate sodiumForm G.

Typical but not limiting conditions for preparing alendronate sodiumForm G are as described in the following table:

Range of Starting Alendronic Preferred Range of Water Acid Hydrate FormSolvent Water Equivalent Equivalent Monohydrate Methanol 20-200 40-175Monohydrate Ethanol 15-100 20-80  Monohydrate Isopropanol 5-40 10-20 Anhydrous Methanol 50-125 80-100 Anhydrous Ethanol 15-40  25-35 

The invention further provides a method for making Form G of alendronatesodium comprising treating any one or more of the crystal forms ofalendronate sodium selected from the group which consists of Form B,Form C, Form D, Form E, Form F and Form H, in a lower alkanol,preferably ethanol, with 20-40 equilvalents of water under theconditions described hereinafter followed by isolating the crystallinealendronate sodium Form G.

The invention further provides a method for making Form G of alendronatesodium comprising treating alendronate monosodium trihydrate in a loweralkanol, preferably ethanol, with 25-35 equivalents of water under thecondition described hereinafter, followed by isolating the crystallinealendronate sodium Form G.

The invention further provides a method for making Form G of alendronatesodium comprising treating any one or more forms of alendronate sodiumsalts preferably selected from the group consisting of monosodium,disodium, trisodium and tetrasodium salts, in a lower alkanol preferablyethanol with 20-40 equivalents of water under the conditions describedhereinafter, followed by isolating the crystalline alendronate sodiumForm G. In the event that the starting sodium salt is higher thanmonosodium (e.g. disodium, trisodium or tetrasodium) it is necessary toadd an acid, preferably alendronic acid, in order to maintain the pH atabout 4.4.

The invention further provides a method for making Form H of alendronatesodium, comprising treating alendronic acid, which is the anhydrous ormonohydrate form, in a lower alkanol with one equivalent of sodium baseand 25 to 35 equivalents of water, under the conditions describedhereinafter, followed by isolating the crystalline alendronate sodiumForm H.

The invention further provides a method for making Form B of alendronatesodium, comprising treating alendronic acid monohydrate in a loweralkanol with one equivalent of sodium base and 0 to 4 equivalents ofwater, followed by obtaining the crystalline alendronate sodium Form B.

The invention further provides a method for making alendronate sodiumdihydrate comprising treating crystalline alendronate sodium trihydratewith an effective amount of drying agent followed by isolating thecrystalline alendronate sodium dihydrate.

The invention further provides a method for making alendronate sodiummonohydrate comprising treating crystalline alendronate sodiumtrihydrate with a sufficient amount of drying agent followed byisolating the crystalline alendronate sodium monohydrate.

The invention further provides a method for making alendronate sodiummonohydrate comprising treating crystalline alendronate sodium dihydratewith a sufficient amount of drying agent followed by isolating thecrystalline alendronate sodium monohydrate.

The invention further relates to a pharmaceutical composition whichcomprises alendronate sodium, having water content of 1.3 to 11.7percent in a therapeutically effective amount, and a pharmaceuticallyacceptable carrier.

The invention further relates to a pharmaceutical composition whichcomprises alendronate sodium in Form B D, E, F, G and/or H in atherapeutically effective amount, and a pharmaceutically acceptablecarrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1a, 1 b, and 1 c show, respectively, the powder X-ray diffractionspectrum, the thermograviometric (TGA) curve and the infrared spectrumof alendronate sodium Form B.

FIGS. 2a, 2 b, and 2 c show, respectively, the powder X-ray diffractionspectrum, the thermograviometric (TGA) curve and the infrared spectrumof alendronate sodium monohydrate Form C.

FIGS. 3a, 3 b, and 3 c show, respectively, the powder X-ray diffractionspectrum, the thermograviometric (TGA) curve and the infrared spectrumof alendronate sodium dihydrate Form C.

FIGS. 4a, 4 b, and 4 c show, respectively, the powder X-ray diffractionspectrum, the thermograviometric (TGA) curve and the infrared spectrumof alendronate sodium Form D.

FIGS. 5a, 5 b, and 5 c show, respectively, the powder X-ray diffractionspectrum, the thermograviometric (TGA) curve and the infrared spectrumof alendronate sodium Form E.

FIGS. 6a, 6 b, and 6 c show, respectively, the powder X-ray diffractionspectrum, the thermograviometric (TGA) curve and the infrared spectrumof alendronate sodium Form F.

FIGS. 7a, 7 b, and 7 c show, respectively, the powder X-ray diffractionspectrum, the then-nograviometric (TGA) curve and the infrared spectrumof alendronate sodium Form G.

FIGS. 8a, 8 b and 8 c show respectively the powder X-ray diffractionspectrum, the thermograviometric (TGA) curve and the infrared spectrumof alendronate sodium of Form H.

DETAILED DESCRIPTION OF THE INVENTION

The invention discloses new hydrate forms of alendronate sodium havingwater contents of 1.3 percent to 11.7 percent.

The present invention also discloses new crystalline forms ofalendronate sodium which have been designated Forms B, D, E, F, G and H.

The term “water content” refers to the content of water based upon theLoss on Drying method as described in Pharmacopeial Forum, Vol. 24, No.1, page 5438 (January-Feburary 1998). The calculation of water contentis based upon the percent of weight that is lost by drying. For Forms Gand H the term “water content” refers to the content of water based upona TGA measurement and a step analysis in the temperature range of about25° C.-215° C. for Form G, and 25° C.-200° C. for Form H.

The term “lower alkanol” refers to alkanols having 1 to 4 carbon atoms.Preferred lower alkanols include ethanol, methanol and isopropanol.

The term “equivalents of water” means molar equivalents of water.

The term “equivalents of sodium base” means molar equivalents of sodiumbase.

Those skilled in the art will appreciate that the term “monohydrate”when used in reference to alendronic acid describes a crystallinematerial having a water content of 6.7%. Those skilled in the art willalso understand that the term “anhydrous” when used in reference toalendronic acid describes alendronic acid that is substantially free ofwater.

One of skill in the art will appreciate that the term “monohydrate” whenused in reference to the monosodium salt of alendronic acid describes acrystalline material having a water content of approximately 6.2%.

One skilled in the art will also appreciate that the term “dihydrate”when used in reference to the monosodium salt of alendronic aciddescribes a crystalline material having a water content of approximately11.7%.

One skilled in the art will also appreciate that the term “1/4 hydrate”when used in reference to the monosodium salt of alendronic aciddescribes a crystalline material having a water content of approximately1.6%.

One skilled in the art will also appreciate that the term “1/3 hydrate”when used in reference to the monosodium salt of alendronic aciddescribes a crystalline material having a water content of approximately2.1%.

One skilled in the art will also appreciate that the term “hemihydrate”when used in reverence to the monosodium salt of alendronic aciddescribes a crystalline material having a water content of approximately3.2%.

One skilled in the art will also appreciate that the term “2/3 hydrate”when used in reference to the monosodium salt of alendronic aciddescribes a crystalline material having a water content of approximately4.2%.

One skilled in the art will also appreciate that the term “3/4 hydrate”when used in reference to the monosodium salt of alendronic aciddescribes a crystalline material having a water content of approximately4.7%.

One skilled in the art will also appreciate that the term “5/4 hydrate”when used in reference to the monosodium salt of alendronic aciddescribes a crystalline material having a water content of approximately7.6%.

One skilled in the art will also appreciate that the term “4/3 hydrate”when used in reference to the monosodium salt of alendronic aciddescribes a crystalline material having a water content of approximately8.1%.

One skilled in the art will also appreciate that the term “3/2 hydrate”when used in reference to the monosodium salt of alendronic aciddescribes a crystalline material having a water content of approximately9.1%.

Finally, those skilled in the art will appreciate that the term“trihydrate” when used in reference to the monosodium salt of alendronicacid refers to a crystalline material having a water content ofapproximately 16.6%.

The term “sodium base” refers to sodium hydroxide and the sodiumalkoxide of a lower alkanol.

Alendronic acid can be prepared by methods that are well known in theart. MI Kabachnik et al., Izv. Akad. Nauk USSR, Ser. Khim, 2, 433 (1978)discloses a reaction for making alendronic acid;

Alendronic acid can also be prepared by the process disclosed in U.S.Pat. No. 4,621,077. It will be appreciated that when alendronic acid isrecrystallized from water, as in the above process, the monohydrate isformed.

Alendronate sodium trihydrate can be prepared by the process disclosedin U.S. Pat. No. 4,922,007.

The contents of all references cited are incorporated by reference.

Alendronic acid monohydrate can be converted to alendronic acidanhydrous by heating in a vacuum oven at 110-220° C. at a vacuum of lessthan 5 mm Hg for 24 hours.

In accordance with the process aspect of the present invention,alendronic acid anhydrous as prepared by any of the known methods isadded to a lower alkanol, preferably ethanol, together with a sodiumbase, preferably sodium hydroxide, and an amount of water that dependsupon the desired crystal form of alendronate sodium. The molar ratio ofsodium base to alendronic acid is 1:1. Those skilled in the art willappreciate that a higher ratio of NaOH would yield the undesirabledisodium and trisodium salts. The reaction mixture is boiled underreflux while being stirred vigorously for approximately 15 hours, untilthe pH of the liquid phase remains constant (approx. pH 7). Crystallinealendronate sodium is then isolated, preferably by filtration aftercooling to ambient temperature, washing with absolute ethanol,optionally washing with absolute ethyl ether and drying overnight in avacuum oven at ambient temperature and at a pressure of 10 mm to 15 mmof mercury. For the purposes of this specification, ambient temperatureis from about 20° C. to about 25° C.

In accordance with the aspects of this invention wherein alendronic acidmonohydrate is converted to,alendronate sodium, alendronic acidmonohydrate as prepared by any of the known methods is added to analkanol, preferably ethanol, together with a sodium base, preferablysodium hydroxide, and a desired amount of water. The amount of waterdepends upon the crystal form that is desired. The molar ratio of sodiumbase to alendronic acid is 1:1. The reaction mixture is boiled underreflux while stirring vigorously for approximately 15 hours, until thepH of the liquid phase remains constant (approx. pH 7). Crystallinealendronate sodium is then isolated, preferably by filtration aftercooling to ambient temperature followed by washing with absoluteethanol, washing with absolute ether and drying overnight in a vacuumoven at ambient temperature and at a pressure of 10 mm to 15 mm ofmercury.

In accordance with the aspects of this invention wherein alendronatesodium trihydrate (Form C) is converted to alendronate sodium dihydrate(Form C), alendronate sodium trihydrate as prepared by methods known inthe art is added to an alkanol which is substantially free of water,preferably absolute ethanol. This mixture is treated with a dryingagent, preferably by refluxing the mixture in a reflux condenser whereinthe condensate formed passes through 3 Å molecular sieves. Theweight:weight ratio of molecular sieves to alendronate sodium trihydrateis preferably about 2:1 and most preferably 12:5. Refluxing of themixture is preferably done for 24 hours with stirring. Alendronatesodium dihydrate is then isolated, preferably by filtration aftercooling to ambient temperature, washing with absolute ether and dryingovernight in a vacuum oven at ambient temperature and at a pressure of10 mm to 15 mm of mercury.

In accordance with the aspects of this invention wherein alendronatesodium trihydrate (Form C) is converted to alendronate sodiummonohydrate (Form C), alendronate sodium trihydrate as prepared by anyof the methods known in the art is added to an alkanol which issubstantially free of water, preferably absolute ethanol. This mixtureis treated with a drying agent, preferably by refluxing the mixture in areflux condenser wherein the condensate formed passed through 3 Åmolecular sieves. If and when a first portion of molecular sieves isexhausted, a second portion of fresh molecular sieves is used. Theweight:weight ratio of molecular sieves to alendronate sodium trihydrateis preferably about 2:1 and most preferably 12:5. Refluxing of themixture is preferably done for 24 hours with stirring. The mixture isallowed to cool to ambient temperature before recharging with anequivalent amount of molecular sieves. Alendronate sodium monohydrate isthen isolated, preferably by cooling to ambient temperature, filtration,washing with absolute ether and drying overnight in a vacuum oven atambient temperature and a pressure of 10 mm and 15 mm of mercury.

In accordance with the present invention, the new crystalline forms ofalendronate sodium and the new hydrate forms of alendronate sodium maybe prepared as pharmaceutical compositions which are particularly usefulfor the treatment of bone resorption in bone diseases includingosteoporosis and Paget's disease. Such compositions may comprise one ofthe new crystalline and hydrate forms of alendronate sodium withpharmaceutically acceptable carriers and/or excipients.

For example, these compositions may be prepared as medicaments to beadministered orally, parenterally, rectally, transdermally, bucally, ornasally. Suitable forms for oral administration include tablets,compressed or coated pills, dragees, sachets, hard or gelatin capsules,sub-lingual tablets, syrups and suspensions; for parenteraladministration the invention provides ampoules or vials that include anaqueous or nonaqueous solution or emulsion; for rectal administrationthere are provided suppositories with hydrophilic or hydrophobicvehicles; and for topical application as ointments or aerosolformulations known in the art; transdermal delivery there are providedsuitable delivery systems as known in the art; and for nasal deliverythere are provided suitable aerosol delivery systems known in the art.

The powder X-ray diffraction patterns were obtained by methods known inthe art using a Philips X-Ray powder diffractometer, Goniometer model1050/70 at a scanning speed of 2° per minute.

The thermogravimetric curves were obtained by methods known in the artusing a Mettler TGA TG50. The weight of the samples was about 10 mg. Thetemperature range was from 25° C. to at least 200° C., at the rate of10° C./min. Samples were purged with nitrogen gas at a flow rate of 40ml/min. Standard 150 ml aluminum crucibles were used.

The infrared spectra were obtained by methods known in the art using aPerkin Elmer FT-IR Paragon 1000 spectrometer. Samples were analyzed inNujol mulls. Spectra were obtained at 4 cm⁻¹ resolution and 16 scanseach.

The atomic absorption analysis was obtained by methods known in the artusing a Perkin Elmer 5000 Flame Atomic Absorption instrument. Sodiumcontent was determined against standard solutions obtained from Merckand Aldrich.

EXAMPLES

This invention will be better understood from the experimental detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims that followthereafter.

Example 1 Preparation of Alendronic Acid Monohydrate

Alendronic acid was crystallized from water to make alendronic acidmonohydrate. The resulting alendronic acid monohydrate was dried at 50°C. at 10 mm Hg pressure for 15 hours to give dry alendronic acidmonohydrate containing 6.9% water.

Example 2 Preparation of Anhydrous Alendronic Acid

The alendronic acid monohydrate from Example 1 was further dried at110-120° C. in 1 mm Hg for 4 hours to give anhydrous alendronic acid.The water content was 0.3% by weight.

Example 3 Preparation of Alendronate Sodium from Anhydrous AlendronicAcid

A 250 ml flask was fitted with a mechanical stirrer, a thermometer, anda reflux condenser. The flask was charged with 41.1 ml of a solution ofsodium hydroxide in ethanol (0.49N, 20.1 mmol), 8.9 ml of ethanol, water(0 to 40 mol. eq., according to the crystal form desired), and 5 g (20.1mmol) of anhydrous alendronic acid. The reaction mixture was boiled withvigorous stirring for about 15 hours until the of pH of the liquid phaseremained constant (approx. pH 7). After cooling of the reaction mixtureto ambient temperature, the solid material was filtered, washed withabsolute ethanol, and dried overnight in a vacuum oven (10-15 mmHg,ambient temperature) to give 96-99% sodium alendronate having thefollowing crystal forms: crystal Form D, when 0-4 (preferably 0-2) mol.eq. water were used; crystal Form F, when 5-8 (preferably 6-7) mol. eq.water were used; crystal Form E, when 9-15 (preferably 12) mol. eq.water were used; and crystal Form G, when 15-40 (preferably 25-35) mol.eq. water were used. The monosodium salt was confirmed by atomicabsorption and by measuring the pH of a 0.5% aqueous solution of thesalt (approx. pH 4.4).

Example 4 Preparation of Alendronate Sodium from Alendronic AcidMonohydrate

A 250 ml flask was fitted with a mechanical stirrer, a thermometer, anda reflux condenser. The flask was charged with 38.2 ml of a solution ofsodium hydroxide in ethanol (0.49 N, 18.7 mmol), 4.8 ml of ethanol,water (0 to 100 mol. eq., according to the crystal form desired), and 5g (18.7 mmol) of alendronic acid monohydrate. The reaction mixture wasboiled with vigorous stirring for about 15 hours until stability of pHof the liquid phase was reached (approx. pH 7). After cooling of thereaction mixture to ambient temperature the precipitate was filtered,washed with absolute ethanol, and dried overnight in a vacuum over(10-15 mm Hg, ambient temperature) to give 96-99% sodium alendronatehaving the following crystalline forms: crystalline Form B, when 0-4(preferably 0-2) mol. eq. water were used; crystalline Form F, when 3-5mol. eq. water were used; crystalline Form E, when 11-13 (preferably 12)mol. eq. water were used; and crystalline Form G, when 15-100(preferably 20-80) mol. eq. water were used.

The monosodium salt was confirmed by atomic absorption and by measuringthe pH of a 0.5% aqueous solution of the salt (approx. pH 4.4).

The water content is determined using the TGA technique, heating thesample to 230° C. and calculating the sharp LOD (loss on drying) step,which occurs above 150° C.

Example 5 Preparation of Sodium Alendronate Dihydrate

A one liter flask was fitted with a magnetic bar stirrer, Soxhletextraction funnel (operating volume 150 ml) charged with 3 Å molecularsieves (60 g), and reflux condenser connected to a drying tube with 3 Åmolecular sieves. The flask was charged with sodium alendronatetrihydrate (25 g) and absolute ethanol (450 ml, vol. % of water<0.1%).The mixture was boiled with stirring for 24 hours. After cooling toambient temperature the solid material was filtered, washed withabsolute ethyl ether, and dried overnight in a vacuum oven (10-15 mm Hg,ambient temperature) to give sodium alendronate dihydrate.

Example 6 Preparation of Sodium Alendronate Monohydrate

A one liter flask was fitted with a magnetic bar stirrer, Soxhletextraction funnel (operating volume 150 ml) charged with 3 Å molecularsieves (60 g), and reflux condenser connected to a drying tube with 3 Åmolecular sieves. The flask was charged with sodium alendronatetrihydrate (25 g) and absolute ethanol (450 ml, vol. % of water<0.1%).The mixture was boiled with stirring for, 24 hours. After cooling toambient temperature, the used molecular sieves were replaced by a newportion of 3 Å molecular sieves (60 g) and the reflux was continued foradditional 24 hours. After cooling to ambient temperature the solidmaterial was filtered, washed with absolute ethyl ether, and driedovernight in a vacuum oven (10-15 mm Hg, ambient temperature) to givesodium alendronate monohydrate.

Example 7 Preparation of Alendronate Sodium Form G from Alendronic AcidMonohydrate

Preparation of aqueous ethanolic sodium hydroxide:

Absolute ethanol (250 ml) and water (59 ml, 35×0.094 mol) were mixed.Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in 45 ml ofthis aqueous ethanol. The remaining aqueous ethanol was used to preparea suspension of alendronic acid monohydrate.

A one liter flask was fitted with a mechanical stirrer, a thermometer,and a reflux condenser. The flask was charged with alendronic acidmonohydrate (25 g, 0.094 mol) and aqueous ethanol. The mixture washeated to boiling with stirring. The aqueous ethanolic sodium hydroxidewas added dropwise to the suspension of alendronic acid monohydrate inaqueous ethanol for 3 hours at reflux with vigorously stirring. Then themixture was stirred at reflux for additional 15 hours. The mixture wascooled to room temperature with stirring. The solid was filtered, washedwith absolute ethanol, then with absolute ethyl ether, and driedovernight in a vacuum oven (10-15 mm Hg, ambient temperature) to give26.2 g of alendronate sodium, having crystalline Form G.

Example 8 Preparation of Alendronate Sodium Form G from Alendronic AcidMonohydrate

Preparation of aqueous ethanolic sodium hydroxide:

Absolute ethanol (250 ml) and water (59 ml, 35×0.094 mol) were mixed.Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in 45 ml ofthis aqueous ethanol. The remaining aqueous ethanol was used to preparea suspension of alendronic acid monohydrate.

A one liter flask was fitted with a mechanical stirrer, a thermometer,and a reflux condenser. The flask was charged with alendronic acidmonohydrate (25 g, 0.094 mol) and aqueous ethanol. The mixture washeated to boiling with stirring. The aqueous ethanolic sodium hydroxidewas added dropwise to the suspension of alendronic acid monohydrate inaqueous ethanol for 3 hours at reflux with vigorously stirring. Then themixture was stirred at reflux for additional 15 hours. The mixture wascooled to room temperature with stirring. The solid was filtered, washedwith absolute ethanol, and dried overnight in a vacuum oven (10-15 mmHg, ambient temperature) to give 26.2 g of alendronate sodium, havingcrystalline Form G.

Example 9 Preparation of Alendronate Sodium Form G from Alendronic AcidMonohydrate

Preparation of aqueous ethanolic sodium hydroxide:

Absolute ethanol (250 ml) and water (59 ml, 35×0.094 mol) were mixed.Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in 45 ml ofthis aqueous ethanol. The remaining aqueous ethanol was used to preparea suspension of alendronic acid monohydrate.

A one liter flask was fitted with a mechanical stirrer, a thermometer,and a reflux. condenser. The flask was charged with alendronic acidmonohydrate (25 g, 0.094 mol) and aqueous ethanol. The mixture washeated to boiling with stirring. The aqueous ethanolic sodium hydroxidewas added dropwise to the suspension of alendronic acid monohydrate inaqueous ethanol for 3 hours at reflux with vigorously stirring. Then themixture was stirred at reflux for additional 15 hours. The mixture wascooled to room temperature with stirring. The solid was filtered, washedwith absolute ethanol, and dried overnight in a vacuum oven (10-15 mmHg, 40-50° C.) to give 26.2 g of alendronate sodium, having crystallineForm G.

Example 10 Preparation of Alendronate Sodium Form G from Alendronic AcidMonohydrate

Preparation of aqueous ethanolic sodium hydroxide:

Absolute ethanol (250 ml) and water (59 ml, 35×0.094 mol) were mixed.Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in 45 ml ofthis aqueous ethanol. The remaining aqueous ethanol was used to preparea suspension of alendronic acid monohydrate.

A one liter flask was fitted with a mechanical stirrer, a thermometer,and a reflux condenser. The flask was charged with alendronic acidmonohydrate (25 g, 0.094 mol) and aqueous ethanol. The mixture washeated to boiling with stirring. The aqueous ethanolic sodium hydroxidewas added dropwise to the suspension of alendronic acid monohydrate inaqueous ethanol for 3 hours at reflux with vigorously stirring. Then themixture was stirred at reflux for additional 15 hours. The mixture wascooled to room temperature with stirring. The solid was filtered, washedwith absolute ethanol, then with absolute ethyl ether, and driedovernight in a vacuum oven (10-15 mm Hg, 40-50° C.) to give 26.2 g ofalendronate sodium, having crystalline Form G.

Example 11 Preparation of Alendronate Sodium Form (G) from AlendronateSodium Trihydrate

A suspension of alendronate sodium trihydrate 1.0 g (3.08 mmol) inaqueous ethanol (10 ml of ethanol+1.9 ml of water) was boiled at refluxwith stirring for 15 hrs. After cooling to ambient temperature the solidwas filtered, washed with absolute ethanol and ether, and driedovernight in a vacuum oven (10-15 mm Hg, ambient temperature) to give0.9 g of alendronate sodium, containing crystal form G.

Example 12 Preparation of Alendronate Sodium Form H from Alendronic AcidMonohydrate

Preparation of aqueous ethanolic sodium hydroxide:

Absolute ethanol (50 ml) and water (6.7 ml, 20×0.019 mol) were mixed.Sodium hydroxide (0.76 g, assay 99%, 0.019 mol) was dissolved in 8.5 mlof this aqueous ethanol. The remaining aqueous ethanol was used toprepare a suspension of alendronic acid monohydrate.

A 250 ml flask was fitted with a mechanical stirrer, a thermometer, adropping funnel, and a reflux condenser. The flask was charged withalendronic acid monohydrate (5 g, 0.019 mol) and aqueous ethanol. Theaqueous ethanolic sodium hydroxide was added dropwise to the suspensionof alendronic acid monohydrate in aqueous ethanol for 15 minutes atreflux with vigorously stirring. The mixture was then refluxed foradditional 15 hours. The mixture was then cooled to room temperaturewith stirring. The solid was filtered, washed with absolute ethanol,then with absolute ethyl ether, and dried overnight in a vacuum oven(10-15 mm Hg, ambient temperature) to give 5.2 g of alendronate sodium,having crystalline Form H.

Although certain presently preferred embodiments of the invention havebeen described herein, it will be apparent to those skilled in the artto which the invention pertains that variations and modifications of thedescribed embodiments may be made without departing from the spirit andscope of the invention. Accordingly, it is intended that the inventionbe limited only to the extent required by the appended claims and theapplicable rules of law.

We claim:
 1. Crystalline monosodium alendronate 2/3 hydrate.
 2. Thecrystalline monosodium alendronate 2/3 hydrate of claim 1 having a watercontent of about 4.2 weight percent.
 3. A crystalline monosodiumalendronate 2/3 hydrate having an X-ray powder diffraction pattern withcharacteristic peaks at 13.1±0.2, 15.2±0.2, 16.3±0.2, 22.3±0.2,22.5±0.2, 23.4±0.2 and 23.7±0.2 degrees 2 theta.
 4. A crystallinemonosodium alendronate 2/3 hydrate having infrared absorption bands at662, 919, 934, 954, 1054, 1072, 1297 and 1318 cm⁻¹.
 5. Crystallinemonosodium alendronate hemihydrate.
 6. Crystalline monosodiumalendronate hemihydrate having an X-ray powder diffraction pattern withcharacteristic peaks at 7.0±0.2, 9.3±0.2 and 14.0±0.2 degrees 2 theta.7. The crystalline monosodium alendronate hemihydrate of claim 6 havingadditional X-ray diffraction peaks at 11.8±0.2, 13.3±0.2, 15.3±0.2,16.2±0.2, 17.4±0.2 and 19.4±0.2 degrees 2 theta.
 8. A Crystallinemonosodium alendronate hemihydrate having infrared absorption bands at660, 897, 924, 953, 970, 1017, 1040, 1093, 1149, 1177, 1252, 1293, 1337,1535, 1606 and 1639 cm⁻¹.
 9. A Crystalline monosodium alendronatehemihydrate form H characterized by x-ray peaks at 9.2±0.2, 14.2±0.2,15.0±0.2, 17.1±0.2, 20.7±0.2, 22.0±0.2, and 22.4±0.2 degrees two theta.10. A Crystalline monosodium alendronate hemihydrate form H havinginfrared absorption bands at 664, 688, 722, 751, 863, 893, 918, 936,984, 1010, 1036, 1052, 1092, 1157, 1273, 1303, 1338, 1499, 1598, 1636and 1664 cm⁻¹.
 11. Crystalline monosodium alendronate Form B.
 12. Thecrystalline monosodium alendronate form B of claim 11 having an X-raypowder diffraction pattern with characteristic peaks at 12.2±0.2,13.3±0.2, 14.8±0.2, 15.8±0.2, 16.3±0.2, 16.6±0.2 and 17.2±0.2 degrees 2theta.
 13. The crystalline monosodium alendronate form B of claim 12having additional X-ray diffraction peaks at 19.4±0.2, 21.3±0.2,22.6±0.2, 23.2±0.2, 24.0±0.2, 25.2±0.2, 25.8±0.2, 27.4±0.2, 29.4±0.2,and 36.0±0.2 degrees 2 theta.
 14. The crystalline monosodium alendronateform B of claim 11 having infrared absorption bands at 654, 955, 1074,1261, 1309, and 1614 cm⁻¹.
 15. A process for preparing a hydrate ofmonosodium alendronate having about 1.3% to about 7.2% water comprisingthe steps of: forming the monosodium alendronate hydrate by reaction ofalendronic acid with a sodium base in suspension in a liquid mediumcomprising a lower alkanol or a mixture of a lower alkanol and water,wherein the liquid medium comprises 3 equivalents or more of water,based on the number of equivalents of alendronic acid, and selectedaccording to, and separating the liquid medium from the crystallinehydrate of monosodium alendronate.
 16. The process of claim 15 whereinthe sodium base is sodium hydroxide.
 17. The process of claim 15 whereinthe crystalline hydrate of monosodium alendronate is formed by providinga solution of the sodium base in a mixture comprising a lower alkanoland water, providing a suspension of the alendronic acid in a mixture ofa lower alkanol and water and contacting the solution and thesuspension.
 18. The process of claim 15 wherein the monosodiumalendronate hydrate is formed by providing a solution of the sodium basein a liquid medium comprising a lower alkanol, providing a suspension ofthe alendronic acid in a liquid medium comprising a mixture of a loweralkanol and water and contacting the solution and the suspension. 19.The process of claim 15 wherein the monosodium alendronate hydrate isformed by providing a solution of the sodium base in a liquid mediumcomprising mixture of a lower alkanol and water, providing a suspensionof the alendronic acid in a lower alkanol and contacting the solutionand the suspension.
 20. A process of claim 15 wherein for making thecrystalline monosodium alendronate 2/3 hydrate of claim 1 comprising thesteps of: a) forming the crystalline monosodium alendronate 2/3 hydrateby reaction of alendronic acid with a sodium base in a liquid medium ofa lower alkanol or a mixture of a lower alkanol and water, and b)separating the liquid medium from the crystalline monosodium alendronate2/3 hydrate.
 21. The process of claim 20 wherein the monosodiumalendronate 2/3 hydrate has an X-ray diffraction pattern withcharacteristic peaks at 13.1±0.2, 15.2±0.2, 16.3±0.2, 22.3±0.2,22.5±0.2, 23.4±0.2 and 23.7±0.2 degrees 2 theta and the liquid medium isa lower alkanol or a mixture of a lower alkanol and water in an amountof about 4 equivalents or less with respect to the alendronic acid. 22.The process of claim 21 wherein the amount of water is about 2equivalents or less with respect to the alendronic acid.
 23. The processof claim 21 wherein the alendronic acid is anhydrous and the amount ofwater is about 2 equivalents or less with respect to the alendronicacid.
 24. The process of claim 15 the crystalline hydrate of monosodiumalendronate has an X-ray diffraction pattern with characteristic peaksat 9.3±0.2, 11.7±0.2, 15.3±0.2, 16.2±0.2, 17.4±0.2 and 25.5±0.2 degrees2 theta and the liquid medium is a mixture of a lower alkanol and watercomprising about 3 to about 8 equivalents of water with respect to thealendronic acid used.
 25. The process of claim 24 wherein the alendronicacid is anhydrous and the amount of water is from about 6 to about 7equivalents with respect to the alendronic acid.
 26. A process formaking monosodium alendronate hemihydrate of claim 5 comprising thesteps of: a) forming the monosodium alendronate hemihydrate by reactionof alendronic acid with a sodium base in a liquid medium of a loweralkanol or a mixture of a lower alkanol and water, and b) separating theliquid medium from the monosodium alendronate hemihydrate, wherein theliquid medium is a mixture of a lower alkanol and from about 9 to about35 equivalents of water with respect to the alendronic acid.
 27. Theprocess of claim 26 wherein the monosodium alendronate hemihydrate hasan X-ray diffraction pattern with characteristic peaks at 7.0±0.2,9.3±0.2 and 14.0±0.2 degrees 2 theta and the liquid medium is a mixtureof a lower alkanol and water in an amount of from about 9 to about 15equivalents with respect to the alendronic acid.
 28. The process ofclaim 27 wherein the alendronic acid is alendronic acid monohydrate andthe amount of water is from about 11 to about 13 equivalents withrespect to the alendronic acid.
 29. The process of claim 27 where theamount of water is about 12 equivalents with respect to the alendronicacid.
 30. The process of claim 26 wherein the liquid medium is a mixtureof a lower alkanol and water in an amount of from about 20 to about 35equivalents with respect to the alendronic acid.
 31. The process ofclaim 30 wherein the amount of water is about 20 equivalents withrespect to the alendronic acid.
 32. The process of claim 30 wherein themonosodium alendronate hemihydrate produces an X-ray powder diffractionpattern with characteristic peaks at 9.2±0.2, 14.2±0.2, 15.0±0.2,17.1±0.2, 20.7±0.2, 22.0±0.2, and 22.4±0.2 degrees two theta.
 33. Theprocess of claim 32 wherein the monosodium alendronate hemihydrate hasinfrared absorption bands at 664, 688, 722, 751, 863, 893, 918, 936,984, 1010, 1036, 1052, 1092, 1157, 1273, 1303, 1338, 1499, 1598, 1636,and 1664 cm⁻¹.
 34. A process for preparing the monosodium alendronatehydrate form B of claim 11 the steps of: forming the monosodiumalendronate monohydrate by reaction of alendronic acid with a sodiumbase in a liquid medium of a lower alkanol or a mixture of a loweralkanol and water, and separating the liquid medium from the monosodiumalendronate monohydrate.
 35. The process of claim 34 wherein thealendronic acid is alendronic acid monohydrate and the liquid medium isa lower alkanol or a mixture of a lower alkanol and water in an amountof about 4 equivalents or less with respect to the alendronic acid. 36.The process of claim 34 wherein liquid medium is a lower alkanol. 37.The process of claim 36 wherein the monosodium alendronate monohydrateis formed by providing a solution of the sodium base in a lower alkanol,providing a suspension of the alendronic acid in a lower alkanol andcontacting the solution and the suspension.